PROJECT SUMMARY Uterine fibroids represent a significant medical challenge with an immense economic burden. With an estimated incidence of 70-80% by the age of 50, they are the most common tumors of the female reproductive tract and the estimated annual costs in the US are $5.9-34.4 billion. Current hormonal treatments have limitations; therefore, there is an urgent need for new non-hormonal therapies. We recently discovered the following: 1) statin (HMG-CoA reductase inhibitors currently used in treating hypercholesterolemia) use was associated with a lower risk of uterine fibroids and fibroid-related symptoms in a retrospective study; 2) simvastatin inhibited tumor growth in a patient-derived xenograft animal model; 3) simvastatin inhibited proliferation and induced apoptosis in human fibroid cells in vitro; and most importantly, 4) the antiproliferative effects of simvastatin and ulipristal acetate on fibroid cells were synergistic. Thus, further evaluation of simvastatin as a treatment for uterine fibroids is needed. While statins are FDA-approved and are in common usage, their effect on fibroids has not been systematically evaluated. We hypothesize that simvastatin has therapeutic effects on leiomyomas, through inhibiting the mevalonate pathway including isoprenoid intermediates necessary for Ras and Rho activation and these effects operate synergistically with ulipristal acetate through modulation of progesterone signaling. The objective of this study is to examine simvastatin as an anti-leiomyoma therapeutic and determine the mechanisms of these effects, in vivo and in vitro. The first aim is a phase II randomized clinical trial to determine feasibility, safety and preliminary clinical efficacy of simvastatin in uterine leiomyoma. The second aim is a translational study to characterize the molecular, cellular and histologic effects of simvastatin on leiomyoma tissues from Aim 1. We expect that simvastatin inhibits proliferation; induces apoptosis, inhibits stem cell proliferation; and alters ECM structure and mechanical signaling in leiomyomas. The third aim will focus on the mechanism(s) of simvastatin?s effects on leiomyoma, including stem cells, growth factor signaling, extracellular matrix production, and sex steroid biosynthesis and signaling. We also examine the mechanisms of synergistic action between simvastatin and ulipristal acetate through modulation of progesterone signaling. The successful completion of this project is the next step toward implementation of a new non-hormonal treatment for uterine fibroids and provides insight into novel therapeutic modulation of critical fibroid pathways. This research proposal is highly response to the RFA and the overall mission of NICHD and NIH.